DESCRIPTION (Abstract): Myeloperoxidase (MPO) has been identified as a risk factor for Alzheimer's disease based on the detection of this myeloid-specific enzyme in amyloid plaques, along with Abeta42, and the association of a n463 G/A promoter polymorphism with increased incidence and earlier onset of disease. MPO catalyzes a reaction between H2O2 and chloride to generate hypochlorous acid (HOCl), a potent oxidant with cytotoxic effects. In normal brain tissue, MPO is not present in the abundant brain microglia, but is present in reactive microglia surrounding plaques in Alzheimer's disease brain, suggesting that MPO gene expression is induced by Abeta or other plaque components. The highest levels of MPO deposition in plaques are detected in ApoE4 carriers, suggesting a link between MPO A allele and ApoE4, the major risk factor for sporadic Alzheimer's disease. Recent genetic evidence further indicates that the MPO A allele and ApoE4 synerigize to increase AD risk for males, while the MPO G allele has been linked to increased risk for females. The n463 G/A polymorphism creates an estrogen receptor-binding site in the MPO A promoter which may form the basis for this gender difference in genotype association with Alzheimer's disease. The experiments in this proposal will further define the role of MPO in Alzheimer's disease, elucidate the mechanism by which MPO and ApoE4 synergize to increase the risk of Alzheimer's disease, and determine the reason for the gender difference in MPO genotype association with AD risk. The experimental design will include analysis of human AD brain tissue, and make extensive use of mouse models expressing genetic risk factors for human Alzheimer's disease. The Specific Aims are: (1) to investigate the mechanism by which MPO contributes to Alzheimer's disease; (2) to investigate the basis for the gender difference in MPO genotype association with Alzheimer's disease; (3) to investigate the mechanism by which ApoE4 and MPO synergize to increase AD risk; and (4) to investigate how the normally quiescent MPO gene is induced in brain microglia in Alzheimer's disease. MPO is a reasonable target for therapeutics aimed at slowing the progression of Alzheimer's disease. An inhibitor of MPO has been previously noted to reduce AD incidence in a large study.